Aminoglycosides are a class of compounds characterized by the ability to interfere with protein synthesis in micro-organisms. Aminoglycosides consist of two or more amino sugars joined in a glycoside linkage to a hexose (or aminocyclitol) nucleus. The hexose nuclei thus far known are either streptidine or 2-deoxystreptamine, though others may be anticipated. Aminoglycoside families are distinguished by the amino sugar attached to the aminocyclitol. For example, the neomycin family comprises three amino sugars attached to the central 2-deoxystreptamine. The kanamycin and glutamicin families have only two amino sugars attached to the aminocyclitol.
Aminoglycosides include: neomycin B, paromomycin, ribostamycin, lividomycin, kanamycin A, kanamycin B, amikacin, tobramycin, viomycin, gentamicin C.sub.1, gentamicin C.sub.1a, (gentamicin C.sub.2, C.sub.1, C.sub.1a and analogs and derivatives thereof collectively "gentamicin"), sisomicin, netilmicin, streptomycin and dihydrostreptomycin. Streptomycin and dihydrostreptomycin characterized by the presence of a gunadino group are understood to be unique in associating with liposomes in higher drug to lipid ratios than the nonguanadino aminoglycosides. The term "nonguanadino" aminoglycosides will include aminoglycosides other than aminoglycosides bearing a guanadino group.
Unfortunately, use of these compounds has been limited by several factors. Often directed to use in preventing protein synthesis in bacteria, bacteria have demonstrated a remarkable capacity to resist the inhibitory effect of aminoglycosides. Resistance of an organism to aminoglycoside action occurs with a broad range of aminoglycosides. A further problem of aminoglycoside use has been characteristically poor gastric absorption and rapid excretion. Injection of aminoglycosides results in rapid peak plasma concentration often in the neighborhood of 30 to 90 minutes following intramuscular injection which is associated with toxicity. Another limitation is that the aminoglycosides fail to enter the CNS or the eye.
In the therapeutic use of aminoglycosides in animals, including humans, serious problems of toxicity have been noted. For example, therapeutic use in higher animals may be accompanied by ototoxicity potentially involving both auditory and vestibular functions as well as nephrotoxicity, and neuromuscular blockade culminating in respiratory distress.
It is an object of this invention to provide an aminoglycoside in the form of a phosphate salt. It is another object of this invention to provide for aminoglycosides with improved liposomal association. It is a further object of this invention to provide a method of manufacture of liposomes associated with aminoglycoside phosphate. It is another object of this invention that said liposomes substantially associate with said aminoglycoside. It is an additional object of this invention that the liposomes of this invention provide a high aminoglycoside to lipid ratio particularly as to nonguanadino aminoglysocides. It is a further object of this invention to provide such liposomes in a pharmaceutical dosage form for therapeutic treatment of an animal including a human.